1. Field of the Invention
This invention is generally directed to sensors for chemical and biomedical analysis of constituents of a fluid or gaseous mixture, and more specifically concerns methods and compositions for manufacturing optical fiber sensors for measuring blood constituents such as oxygen, carbon dioxide, and pH.
2. Description of Related Art
Optical fiber sensors for measuring pH, oxygen and carbon dioxide have been developed for in vivo, intravascular measurements of blood constituents, such as pH, oxygen and carbon dioxide. Fluorescence dye indicators whose fluorescence emissions are affected by the blood constituent can be incorporated in a semipermeable polymeric matrix to be attached to an optical fiber to provide highly sensitive sensors. A light source provides a selected wavelength of light which propagates down the optical fiber to excite the dye to fluoresce. The intensity of the fluorescence of the dye is a function of the analyte level in the sample, and can be measured to give an indication of the concentration of the blood constituent.
A fluorescent sensor typically utilizes light in one wavelength region to excite the fluorescent indicator dye to emit light of a different wavelength. A pH sensor may utilize a single dye that exists in acid and base forms, each having a different excitation wavelength. The concentration of carbon dioxide in a sample can similarly be based upon measurement of the pH of a solution of bicarbonate in equilibrium with carbon dioxide from the sample. The bicarbonate and carbon dioxide form a pH buffer system in which the hydrogen ion concentration generally varies with the carbon dioxide concentration. In this manner, the pH or carbon dioxide content of a solution may be measured with dyes such as fluorescein or 8-hydroxy-1, 3, 6 pyrenetrisulfonic acid (HPTS).
Blood oxygen content can similarly be measured with fluorescence quenching techniques which utilize an oxygen-quenchable fluorescent dye that is incorporated in a gas permeable matrix. The intensity of the fluorescence of the dye is a function of the oxygen level in the sample, and can thus be used to measure blood oxygen partial pressure.
In order to be useful for intravascular measurements of blood constituents, such sensors are typically quite small. Such optical fiber microsensors are typically manufactured individually, and are generally complex and difficult to manufacture. Moreover, the prepolymers used for preparation of the dye polymer matrix of the sensors typically polymerize quite rapidly when mixed, so that only small batches can be usefully prepared at a time for construction of a limited number of sensors. An indicator dye is commonly incorporated in a liquid polymeric matrix and the liquid matrix material is converted to a solid matrix in situ on the optical fiber. In one suggested method a vinyl-functional base polymer and crosslinking mixture are deposited in a capillary tube extension at the tip of an optical fiber. A photosensitive initiator causes the mixture to crosslink upon exposure to actinic radiation, to initiate formation of a gel. Unfortunately, the dye, which can be quite toxic, is retained in the gel matrix only by electrostatic forces. This allows the dye to leach out of the sensor, which can produce toxic reactions in the blood stream, and leads to depletion of the dye, with consequent depletion of the intensity of the fluorescence signal.
In another method for fabricating a CO.sub.2 microsensor, an aqueous dye-buffer solution and a hydrophobic polymeric precursor with a crosslinking agent and a catalyst are emulsified and allowed to cure. However, the rate of crosslinking is quite rapid, particularly in the presence of the catalyst, and no allowance is made for controlling the rate of cure. This normally results in a short period of working potlife for the liquid matrix material, and represents a barrier to automation of the fabrication process.
In another method of fabricating a pH microsensor, a derivative of cellulose to which a pH sensitive dye is attached is dissolved in hydroxide salts of heavy metals in a diamine or ammonia solution, and regenerated in situ on the optical fiber tip, upon exposure to a dilute acid. The dye matrix is then coated with a mixture of cellulose acetate and carbon black for optical isolation of the sensor. However, the heavy metal elements of the solvent system are incompletely removed, and may leach from the microsensor in blood.
It would therefore be desirable to provide for an improved method for controlling the rate of crosslinking of prepolymers used in forming a stable sensing matrix for such optical fiber sensors, so that the sensing matrix material can be stored for long periods of time in an uncured state and cured on demand to facilitate automation of the manufacturing process.